Regenerative medicine is an applied field of tissue engineering that focuses on the regeneration of damaged tissues of the body. Applications of regenerative medicine include the reconstruction or replacement of organs such as the bladder.
Many diseases and injuries can lead to damage or loss of the bladder, requiring repair or replacement of the organ. Children with congenital abnormalities such as bladder exstrophy, posterior urethral valves, or myelomeningocele (commonly known as spina bifida) can develop high-pressure and hypertonic low-compliant bladders. In the adult population, bladder cancer is the fourth most commonly diagnosed malignancy in men and the ninth most commonly diagnosed malignancy in women in the United States.
The fundamental function of the bladder is to provide a capacious reservoir that can store urine under low pressure and empty under volitional control. Patients suffering from afflictions that involve a loss of bladder function experience a dramatic, negative alteration in their quality of life, and are at risk for hydronephrosis and renal failure.
Bladder reconstruction, or cystoplasty, is often indicated when drug treatments are inadequate. Currently, augmentation cystoplasty is usually accomplished by placing a detubularized segment of intestine onto the bladder. Although functional, several complications can arise from using intestinal segments or gastric flaps for urinary reconstruction. Deleterious side effects include infection, intestinal obstruction, mucus production, electrolyte abnormalities, perforation, and carcinogenicity. Therefore a more clinically applicable process of bladder reconstruction through tissue-engineered regeneration is needed.
Advances in tissue engineering have demonstrated that bladder regeneration is possible through the use of biodegradable membranes seeded with primary cultured cells (Kropp, et al. (1996) J. Urol. 156:599; Atala, et al. (1992) J. Urol. 148:658; Oberpenning, et al. (1999) Nat. Biotechnol. 17:149). The feasibility of this concept has been demonstrated in humans, and bladder regeneration and the enlargement of bladder volume were accomplished (Atala et al. (2006) The Lancet 367:1241-46).
Biomaterial scaffolds that have been used to achieve successful bladder regeneration include acellular collagen matrixes and synthetic polymers. Collagen matrixes include porcine bladder submucosa membrane (BSM) and small intestine submucosa (SIS), which both contain numerous natural components required for normal cell growth, differentiation, and functioning, including collagen, glycoproteins, proteoglycans, and functional growth factors (Hodde, et al. (2001) Endothelium 8:11; Voytik-Harbin, et al. (1997) J. Cell. Biochem. 67:478). Synthetic polymers scaffolds include polyglycolic acid (PGA), polylactic acid (PLA) and polylactic-co-glucolic acid (PLGA) (Oberpenning, et al. (1999) Nat. Biotechnol. 17:149; Atala, et al. (1993) J. Urol. 150:608).
Autologous bladder cells are the most commonly used cell source for tissue engineered constructs in patients who do not have cancer. A patient's own cultured cells seeded onto a bio-material scaffold can act as a framework for regenerating tissues. To obtain the bladder cells, however, invasive tissue biopsy procedures are performed for cell harvest, which increase medical care expenditures and are associated with potential complications such as bleeding, infection, and urethral or bladder injury. In addition, cells obtained from bladder biopsy sometimes fail to grow due to mucosa tissue disruption before or during biopsy (Zhang & Frey (2003) Adv. Exp. Med. Biol. 539:907).
Alternative cell sources are being investigated for urologic reconstruction, including embryonic, fetal and adult stem cells. Stem cells are self-renewing and not terminally differentiated, and therefore can produce various types of cells. Human embryonic stem cells are promising for tissue engineering purposes (Frimberger, et al. (2005) Urology 65:827; Lakshmanan, et al. (2005) Urology 65:821), but questions of immunocompatibility, tumor formation, and ethics remain. Fetal or adult stem cells are found only in very sparse numbers in the host tissue, may not expand well in culture, and have a more restricted differentiation potential (Vogel (2001) Science 292:1820). Therefore, current clinical use for stem cells in tissue engineering may be limited.
More preferable alternatives to autologous cell harvest through biopsy are needed for urological tissue engineering and cell therapy, particularly where autologous cells are not available for biopsy.